I

n
n
o
v
a
t
i
o
n
s

i
n

P
h
a
r
m
a
c
e
u
t
i
c
a
l

T
e
c
h
n
o
l
o
g
y
I
s
s
u
e
2
3


A
u
t
u
m
n
2
0
0
7
Innovations in Pharmaceutical Technology
Autumn 2007
EARN YOUR
STRIPES
Zebrafish swim to
prominence in the
drug discovery arena
SPECIAL
DELIVERY
Auto-injectors
put an end to
needlestick injuries
FINDING CLOSURE
New vial technology
revitalises the injectable
drug market
AUTOMATED
ANSWERS
Pharma production
technology benefits
from robotics
EARN YOUR
STRIPES
Zebrafish swim to
prominence in the
drug discovery arena
SPECIAL
DELIVERY
Auto-injectors
put an end to
needlestick injuries
FINDING CLOSURE
New vial technology
revitalises the injectable
drug market
AUTOMATED
ANSWERS
Pharma production
technology benefits
from robotics
CPhI Worldwide/ICSE/P-MEC issue
IPT 23 Cover 31/8/07 13:58 Page 1
Lyophilisation is the process of drying a product in a
frozen state under vacuum to increase product stability,
minimise the effects of oxidation and degradation,
and increase the shelf-life of the product. The process
has found application for preserving products
including biologicals, bacterial cultures, water-damaged
documents, tissue preparations, food and therapeutic
products such as vaccines, drugs, antibodies and
proteins. The continuing discovery and development of
protein-based therapeutics is driving an increasing need
for improvements in freeze-drying process development.
PROCESS DEVELOPMENT CHALLENGES
Major challenges in lyophilisation are the development
of an optimised lyophilisation cycle, and scale-up of the
lyophilisation cycle from a laboratory to a pilot- or
production-scale unit. Understanding the characteristics
of the product and the lyophiliser performance are
crucial for successful freeze-drying. Many products that
are candidates for freeze-drying such as protein-based
therapeutics are in short supply and can be very
expensive to produce. Lyophilisation is a time- and
energy-intensive process that can take days and weeks to
complete. Shortening the lyophilisation cycle
development process to produce an optimised
lyophilisation cycle can increase efficiency, accelerate
development time and thus reduce time-to-market, and
save valuable product. Transfer of an optimised
lyophilisation cycle from the development stage to
production scale should provide the most efficient drying
cycle, thus further increasing the return on investment.
The lyophilisation process consists of first freezing the
product to a temperature at which all formulation
components form a rigid solid. This is followed by
primary drying, in which up to 95% of the frozen water
or ice is removed. During primary drying, controlled
temperature shelves are utilised to provide the energy for
sublimation of the ice. In turn, the pressure in the
chamber must also be controlled in a way that heat can be
added to the product to facilitate sublimation of the water,
without causing melting or instability of the already dried
product matrix. The sublimated water vapour from the
product travels into the product chamber, and is
transferred to the condenser due to the pressure
differential between the product chamber and the
condenser; it is then frozen onto the coils or plates in the
condenser, thus helping the condenser to remain in a low
pressure condition relative to the product chamber (1).
Any remaining water not removed during primary drying
is removed during a secondary, desorption drying step.
Critical parameters in developing a lyophilisation
cycle and thus successful freeze-drying include
knowing the collapse temperature of the formulation,
the stability of the active pharmaceutical ingredient and
the properties of the excipients (2). In addition to
properties of the formulation, shelf temperature,
chamber pressure, system geometry and the product
container all play major roles in lyophilisation cycle
development. Many lyophilisation processes are
developed in a trial-and-error manner that often results
in non-optimised lyophilisation cycles that may not
transfer well from the laboratory to production scale-up.
ACCELERATING LYOPHILISATION
CYCLE DEVELOPMENT
At SP Industries, we have commercialised a technology
(FTS SMART Freeze-Dryer
TM
Technology) for
accelerating and streamlining the development of
lyophilisation cycles. Created through a partnership
between the University of Connecticut and Purdue
University, and partially funded through the Center for
Pharmaceutical Processing Research (CPPR), the
technology, run on an FTS LyoStar II System (see Figure
1, page 88), provides both experienced and new
87
Innovations in Pharmaceutical Technology
Ingredients, Formulations & Finishing
By Debra Sesholtz and Leslie Mather at SP Industries
Debra Sesholtz joined SP Industries in 2005 as Director of Corporate Marketing. She has more than 20 years
experience with roles in technical support, sales and marketing of scientific equipment and consumables to the
pharmaceutical, biotechnology, life science and chemical industries.
Leslie Mather is the Product Manager for R&D Lyophilisers at SP Industries. She joined FTS Systems, now part of SP
Industries, in 1998. For the past nine years, she has been responsible for product development, sales and technical
support. Ms Mather holds a BS from Cornell University.
Smart Freeze-Drying
By removing the trial-and-error element from developing lyophilisation
processes, a new technology enables users to optimise lyophilisation cycles
and ensure the smooth transfer from laboratory- to production-scale.
IPT 23 2007 30/8/07 10:51 Page 87
lyophilisation scientists with a means of developing
optimised lyophilisation cycles with a reduction in
average cycle development-time of up to 78%,
based on independent testing results. The
technology reduces the average cycle development
process to one or two runs, rather than the
conventional series of six to eight runs thereby
not only reducing development time, but also
reducing materials costs by one-third or more. This
leaves the development scientist with more time
for studying other factors contributing to an
optimised lyophilisation cycle such as excipient
choices and parameter extremes, and their subsequent
effect on the freeze-dried product.
The principle behind the technology is the use of
manometric temperature measurement (MTM). This
delivers an accurate calculation of the product
temperature at the sublimation interface, without having
to place thermocouples or other temperature sensors in
the product vials. Measurement of the product
temperature at the sublimation interface is critical for
determining the correct parameters for preventing
product collapse or melt back during primary drying.
The conventional method for measuring product
temperature during a freeze-drying cycle is to place a few
selected temperature sensors in vials. Note, however, that
this may affect the freezing and drying behaviour of the
samples by inducing ice nucleation or acting as a thermal
pathway. These issues make placing a thermocouple in a
vial a poor representation for what is actually occurring
in the majority of vials present in the product chamber.
In addition, temperature sensors or thermocouples
placed in vials are located towards the bottom of the vial
not at the sublimation interface and therefore do not
give an accurate a measurement of product temperature
at the sublimation-ice interface (1). Thermocouples are
sometimes difficult to repeatedly place in the same
position, and have their own inherent inaccuracies across
their temperature range.
With the MTM technique, an isolation valve is
placed between the product drying chamber and the
freeze-dryer condenser. Input parameters prior to
running a SMART lyophilisation cycle include the
number of product vials, the fill-volume of the vials,
whether the product is amorphous or crystalline, and the
collapse temperature or eutectic point of the product.
During execution of the lyophilisation cycle, the
isolation valve is rapidly and automatically closed, and
the rise in pressure is measured for 25 seconds at regular
intervals during primary drying. The raw data is
accumulated and used in the MTM equation to calculate
the product temperature at the ice surface interface, the
dried layer resistance, the ice thickness, and the heat flow
and mass transfer.
This information is then applied to automatically
adjust the shelf and vacuum set-points of the lyophiliser
during freeze-drying, thus achieving and maintaining the
product temperature precisely at the target temperature
throughout the lyophilisation cycle.
In practice, in order to get good MTM data, a
minimum product surface area of greater than 300 square
centimeters or three-quarters of a sample tray is required.
Other requirements include the lyophilisation system
being relatively leak-free, the sample being in an aqueous
solvent, the recommended solids content being between
three and 15 per cent and the optimal vial fill being one-
third the volume of the selected product container.
CRITICAL PARAMETERS
IN CYCLE DEVELOPMENT
One of the critical parameters for successful cycle
development using SMART Freeze-Dryer Technology is
the temperature at which the product needs to be
maintained throughout the primary drying phase. This
critical temperature is determined from either the glass
transition temperature of the product (T
g
) or the collapse
temperature (T
c
) (3). These values are most commonly
determined by differential scanning calorimetry (DSC)
or freeze-dry microscopy. The precision of the input
parameters for set-up of a SMART lyophilisation cycle
will determine the quality of the MTM fit and therefore
the resultant lyophilisation process design.
Figure 2 summarises the steps in SMART Freeze-Dryer
Technology operation. Based on user input, an initial
temperature and pressure are automatically chosen by the
software. After transitioning to primary drying, MTM
measurements begin and are fed into the SMART
algorithms to determine the product temperature at the
sublimation surface. The software provides real-time data
on the product resistance, ice thickness and heat transfer
88
Innovations in Pharmaceutical Technology
Figure 1: An
FTS LyoStar II
running SMART
Freeze Dryer
TM
Technology
Figure 2:
The SMART
Freeze-Dryer
Technology
Process
Step 1: Initial temperature
and pressure are automatically
chosen by SMART
Step 2: After transitioning
to primary drying, MTM
measurements and SMART
algorithms accurately determine
product temperature (Tp) at ice
surface without thermocouples
Step 3: SMART provides
critical real-time data on
product resistance, ice
thickness and heat flow
during primary drying
Step 4: SMART uses these process
measurements to automatically adjust
shelf temperature and chamber pressure
to achieve and maintain optimal product
temperature throughout primary drying
Step 5: SMART
detects the end of
primary drying and
automatically proceeds
into secondary drying
Step 6: SMART delivers
optimised cycle along with
rich body of process data
IPT 23 2007 30/8/07 10:51 Page 88
1ry the new 5MAR1 R0t ca|cu|ater
at www.Itssystems.cem{smartca|c
er ca||: urepe: +oo :o zoee
U5A: +: 8o-68-ee:
SP Industries, Inc. 2007
keduce freeze-dry cycIe
deveIepment time by jo%
lntreducing 5MAk1 lreeze-Bryer

1echneIegy
SMAk1 is cvcilcblc cs
c rctrcht cr cr rcw
lvcStcr

ll k80 crJ
Prcrcss 0cvclcpmcrt
Frcczc-0rvcrs.
1ime te 0eve|ep 0ne
freeze-0rying Cyc|e
6z 0ays
1 0ays
SMAkT
Conventlonal
Annua| 0irect
0eve|epment Cests
$,o/
$cc/,zSc
SMAkT
Conventlonal
8ased on reported averaee of S
development proerams per year.
kesults are based on lndependent
testlne at customer sltes.
5MAR1 freeze-0ryer 1echne|egy
enables skllled development sclentlsts to
accelerate and streamllne the development
of freeze-drylne cycles for proteln-based
therapeutlcs.
Case studles from several premler llfe
sclences oreanlzatlons lndlcate
breakthroueh results:
Cycle development tlme reduced
by /% or more.
Annual cycle development cost
savlnes of $co,ooo or more.
Process data, such as product
reslstance and heat fow, avallable
at the push of a button.
0ays shaved off freeze-drylne cycles.
PAT capabllltles help understand
process varlables, support scale-up
and answer reeulatory
questlons.
An SP Industries Brand
IPT 23 2007 30/8/07 10:52 Page 89
flow during primary drying (see Figure 3). Using these
process measurements, the shelf temperature and drying
chamber pressure are automatically adjusted to maintain the
optimal product temperature throughout primary drying.
The end of primary drying is then detected and the process
then automatically progresses into secondary drying. At the
end of the process, an optimised lyophilisation cycle is
delivered, along with all the process data.
Figure 4 gives results from two case studies of process
development savings that were achieved by applying
SMART Freeze-Dryer Technology. Both laboratories
reported breaking even on their investment in new
technology in less than three months. Primary savings
were achieved through the ability to deliver an optimised
lyophilisation cycle after just a few experimental runs.
The average cycle-development time was reduced by 62
days or 78%. Development savings primarily in labour
and active ingredient material costs averaged $40,029;
with an average of eight development programs per year,
the average annual savings is $320,232.
CONCLUSION
SMART sample data output not only affords an
optimised freeze-drying cycle, but also provides the user
with the MTM data to better understand the freeze-
drying process and troubleshoot freeze-drying protocols.
Pharmaceutical manufacturers are being encouraged by
the FDA through their process analytic technology
(PAT) initiative (4,5) to understand and control process
parameters to build quality into product manufacturing
by design. SMART Freeze-Dryer Technology is a PAT
tool for identifying and reporting critical parameters
during the product freeze-drying formulation process
that can be later monitored during freeze-drying
production to maintain product quality.
Developments are underway to improve the
technology as a PAT tool. These improvements will allow
MTM measurements to be collected on standard or
currently-used freeze-drying cycles. Scientists will be able
to run their standard freeze-drying cycles and collect
MTM data including resistance measurements, product
temperature calculations and heat-flow calculations. This
additional data will provide significant advantages in
trouble-shooting existing freeze-dryer cycles, and
validating changes or adjustments to legacy protocols.
There continues to be an increasing need for
improved methods in freeze-drying process development
especially with the continuing advancements in
protein-based therapeutics. This, coupled with the FDAs
PAT initiative, make the development of tools such as
SMART important in developing robust freeze-drying
protocols, and providing the critical data needed to
identify parameters that require monitoring and
controlling during product production.
The authors can be contacted at
leslie.mather@spindustries.com
References
1. Tang, X., Nail, S.L., Pikal, M.J. Evaluation of
Manometric Temperature Measurement, a Process
Analytical Technology Tool for Freeze-Drying: Part I,
Product Temperature Measurement. AAPS
PharmeSciTech 2006, 7(1), E1-E9.
2. Tang, X., Pikal, M.J. Design of Freeze-Drying Processes
for Pharmaceuticals: Practical Advice. Pharmaceutical
Research 2004, 21(2), 191-200.
3. Gieseler, H., Lee, H., Mulherkar, B., Pikal, M.J.
Applicability of Manometric Temperature Measurement
(MTM) and SMART Freeze Dryer Technology to
Development of an Optimized Freeze Drying Cycle:
Preliminary Investigations of Two Amorphous Systems.
1st European Congress on Life Science Process
Technology 2005, October 11-13, Nuremberg, Germany.
4. U.S. FDA Center for Drug Evaluation and Research,
http://www.fda.gov/Cder/OPS/PAT.htm
5. Gieseler, Henning, PAT for freeze drying: cycle
optimization in the laboratory. European Pharmaceutical
Review 2007, Issue 1, 62-67.
90
Innovations in Pharmaceutical Technology
Figure 3: The SMART
Freeze-Dryer software
provides real-time
data on the product
resistance, ice thickness
and heat transfer flow
during primary drying
Figure 4: Results from
two case studies of
process development
savings that were
achieved by applying
SMART Freeze-Dryer
Technology
Case #1 detail
Traditional approach SMART approach Savings
Number of experimental runs performed 10 2 8
Estimated development time (days) 95 19 76
Analytical (DSC) costs $1,000 $1,000 $0
Labour costs $36,060 $2,412 $33,648
Material costs $93,750 $75,000 $18,750
Total costs per development programme $130,810 $78,412 $52,398
Development programmes per year 8 8 -
Total annual cycle development costs $1,046,480 $627,296 $419,184
Case #2 detail
Traditional approach SMART approach Savings
Number of experimental runs performed 8 2 6
Estimated development time (days) 63 16 47
Analytical (DSC) costs $1,000 $1,000 $0
Labour costs $30,480 $2,820 $27,660
Material costs $25,000 $25,000 $0
Total costs per development programme $56,480 $28,820 $27,660
Development programmes per year 8 8 -
Total annual cycle development costs $451,840 $230,560 $221,280
IPT 23 2007 30/8/07 10:52 Page 90